The present invention, in some embodiments thereof, relates to ophthalmic and ocular devices, and more particularly, but not exclusively, to multifocal ophthalmic devices made of polymeric or co-polymeric compositions.
Light is an electromagnetic wave emitted by excited electrons; and as such can reflect, refract and diffract.
The human eye is a complex anatomical device, which evolved to interact with light and facilitates interpretation of shapes, colors, dimensions and relative position of objects by processing the light they reflect or emit. Similarly to a camera, the eye is able to refract light and produce a focused image that can stimulate neural responses and provide the ability to see. The iris regulates the amount of light admitted to the interior of the eye, the cornea and the lens focus the light rays from an object being viewed onto the retina which transmits the image of the object to the brain via the optic nerve. About 75% of the focusing is provided by the cornea, with the other 25% provided by the crystalline lens which may acquire variable focal lengths.
The cornea is the most anterior structure of the eye. Since it has to be transparent to allow light to enter the eye, there are no blood vessels in the cornea. The cornea is composed of collagen fibers packed together in an organized pattern, thereby providing the cornea its light transparent nature. The cornea has the highest concentration of nerve endings in the entire body, thus making it extremely sensitive to any kind of trauma. The front view of the cornea is of an aspheric shape, where the vertical dimension is smaller than the horizontal dimension by about 1-2%. The anterior is typically about 11.7 mm in diameter.
The quality of vision depends on many factors including the size and shape of the eye, and the transparency of the cornea and lens. When age or disease causes the lens to become less transparent, vision deteriorates because of the diminished light which can be transmitted to the retina. This deficiency in the lens of the eye is medically known as a cataract. An accepted treatment for this condition is a surgical replacement of the lens.
Corrective optic devices are used to correct refractive errors of the eye by modifying the effective focal length of the lens in order to alleviate the effects of conditions such as nearsightedness (myopia), farsightedness (hyperopia) or astigmatism. Another common condition in older patients is presbyopia which is caused by the eye's crystalline lens losing transparency (cataract) and/or elasticity, progressively reducing the ability of the lens to accommodate, namely to focus on objects close to the eye.
Corrective optic devices, also referred to herein as ophthalmic devices, include, for example, contact lenses and IOLs (intraocular lens, an implanted lens in the eye, usually replacing the existing crystalline lens because it has been clouded over by a cataract, or as a form of refractive surgery to change the eye's optical power), keratoprostheses, corneal rings, phakic lenses, aphakic lenses, capsular bag extension rings, corneal inlays and corneal onlays. Corrective optic devices for refractive errors also include eyeglasses, sunglasses or spectacles, comprising frames bearing lenses which are worn in front of the eyes normally for vision correction, eye protection, or for protection from UV rays.
Ophthalmic devices include cornea implants for artificial keratoplasty (keratoprostheses), cornea onlay lenses (contact lenses) or corneal inlay lenses or rings for correcting refractive errors, intraocular lenses for cataract surgery, phakic intraocular lenses in the posterior chamber of eye and lenses for optical instruments. Generally, such devices operate accordion to the refraction and/or diffraction principles stemming from their shape and composition.
Contact lens is a corrective, cosmetic, or therapeutic lens usually placed on and in contact with the cornea of the eye, hence the name contact lens. Contact lenses usually serve the same corrective purpose as eyeglasses, but are typically soft, lightweight and virtually invisible (some commercial lenses are tinted a faint blue to make them more visible when immersed in cleaning and storage solutions). Some cosmetic lenses are deliberately colored to alter the appearance of the eye. Some contact lenses have a thin surface treatment which is a UV-absorbing coating; this helps to reduce UV damage to the eye's natural lens. It has been estimated that 125 million people use contact lenses worldwide (2%).
Ophthalmic implants (also referred to herein as implantable ophthalmic devices), such as intraocular lenses, differ from contact lenses mainly by their permanent placement in the eye. Intraocular lenses (IOL), also known as implantable contact lenses, are special small corrective lenses surgically implanted in the eye's posterior chamber behind the iris and in front of the lens to correct higher degrees of myopia and hyperopia. When age or disease causes the lens to become less transparent, vision deteriorates because of the diminished light which can be transmitted to the retina. This deficiency in the lens of the eye is medically known as a cataract. An accepted treatment for this condition is surgical removal of the lens and replacement of the lens function by an intraocular lens. Implantable ophthalmic devices can be surgically implanted into a living cornea, or in other cases, are located in proximity to a damaged living cornea. It is highly desirable, even essential, for the long term viability of such corrective lens structure onlays or implants, that the material constituting these devices be chemically and physically stable and capable of sustaining and possible filtering damaging radiation. Typically, this material is a polymer or co-polymer of some sort.
Over the years, numerous types of IOLs have been developed for correcting vision deficiencies. Generally, such lenses operate accordion to one or two basic optical principles: refraction and diffraction.
A typical optical device is manufactured from a polymeric composition, has a diameter of about 5-7 mm, and is supported in the eye by the spring force of flexible loops called haptics.
Multifocal lens has more than one point of focus. A bifocal, which is a type of multifocal, has two points of focus, one at distance and the other at near. In multifocal IOL the aim is to increase the range of distinct vision and hence to reduce the dependence on additional spectacle corrections. Rigid lenses that have two or more optical powers are used to divide the incident light between axially separated images. Overall image quality is affected by the number of lens powers, and the image quality of the focused component itself.
One type of multifocal IOL is diffractive multifocal IOL. A pair of diffraction orders is used to provide two lens powers simultaneously by using rigid implant. One power is used for distance vision and the other power is used for near vision. In both cases defocused light is also incident on the retina, but the human visual system is tolerant of contrast-related image variations and this does not appear to be a problem for most patients. The diffractive design utilizes the full aperture and is tolerant of pupil size variations and modest decentration.
Generally, a diffractive lens consists of any number of annular lens zones of equal area. Between adjacent zones optical steps are provided with associated path length differences which usually are absolutely smaller than a design wavelength. The area or size of the zones determines the separation between the diffractive powers of the lens; this separation increases with decreasing zone area. The optical path difference determines the relative peak intensities of the various diffractive powers. For example, when the optical path difference equals half the wavelength there are two principal diffractive powers, the zeroth and the first order diffractive power. For absolute path differences which are smaller than half the wavelength, the zeroth order power is dominant, while for optical path differences which are of order of one wavelength the first diffractive order power is dominant.
Also known are lenses which are based on refractive principles. Such refractive lenses typically include concentric zones of differing power.
U.S. Pat. No. 4,338,005 discloses a multiple focal power optical device which includes a plurality of alternating annular concentric zones. At least some of the zones include focal power means for directing incident parallel light to a first focal point, and at least some of the zones include focal power means for directing incident parallel light to a second focal point. The radius of the nth zone is proportional to the square root of n, and the radius of the first zone is proportional to the square root of the wavelength under consideration.
U.S. Pat. No. 5,089,023 discloses an intraocular optical implant which includes a refractive/diffractive lens having an anterior surface and a posterior surface and a generally anterior-posterior optical axis. At least one of the anterior and posterior surfaces of the lens has a diffractive lens profile covering about half the effective lens area of the lens.
U.S. Pat. No. 5,699,142 discloses a diffractive multifocal ophthalmic lens having an apodization zone that gradually shifts the energy balance from the near focus to the distance focus over a substantial portion of the lens so that the outer region of the lens directs all of its energy to the distance focus.
U.S. Pat. No. 6,536,899 discloses a multifocal lens including a plurality of annular zones. Each annular zone is divided into two annular sub-zones such that the refractive powers within the sub-zones exhibit at least two diffractive powers and at least one of the diffractive powers substantially coincides with the average refractive power of each annular zone.
Additional background art includes U.S. Pat. Nos. 4,881,805, 5,344,47, 7,377,641, 4,162,122, 4,210391, 4,338,005. 4,340,283, 4,995,714, 4.995,715, 4,881,804, 4,881,805, 5,017,000, 5,054.905, 5,056,908, 5,120,120, 5,121,979, 5,121,980, 5,144,483, 5,117,306, 5,076,684, 5,116,111, 5,129,718, 4,637,697, 4,641,934 and 4,655,565, and European Patent No. 1194797B1.
In general, the material used for ophthalmic implants is required to be and to remain stable in prolong exposure to wear and UV light, and remain transparent and substantially glistening-free and vacuoles-free for extended periods of time at the physiological conditions of the eye, namely in contact with the eye's living tissue, tear enzymes and 37° C. A typical IOL is manufactured from polymethyl methacrylate, has a diameter of about 5-7 mm, and is supported in the eye by the spring force of flexible loops called haptics. Other materials are also used, and there are a variety of lens style and haptic designs.
Most contemporary contact optical devices, such as contact lenses and ophthalmic implants which are used for small incision cataract surgery, require foldable materials like hydrophilic and hydrophobic acrylics and silicones; however, hydrophilic acrylic/hydrogel suffers with incompatibly low refractive index (RI) and high posterior capsular opacification (PCO) rate. Other mechanical characteristics also contribute to this incompatibility, such as the springiness of silicon-based materials, which may result in corneal endothelium damage and/or rupture of capsular bag. Polymeric compositions such as hydrophobic acrylics are more desirable as these are typically characterized by higher RI allowing smaller incision cataract surgery, minimal chances of PCO and controlled elasticity.
Thus, ophthalmic devices made from polymeric compositions should be transparent, flexible, deformable, glistening-free, vacuoles-free, contaminant-free (leachables), have low tackiness, low internal reflections, characterized by low stress generation or local burning while machining, and other handling and manufacturing problems.
WO 1994/011764 teaches foldable intraocular lenses made from polymeric compositions of high refractive index, comprising a copolymer including a first constituent derived from a first monomeric component the homopolymers of which have a refractive index of at least about 1.50, a second constituent derived from a second monomeric component other than the first monomeric component the homopolymers of which have a glass transition temperature of less than about 30° C., a third constituent derived from a crosslinking monomeric component in an amount effective to facilitate returning a deformed intraocular lens made of these compositions to its original shape, and a fourth constituent as a hydrophilic monomer. However WO 1994/011764 is silent with respect to the superfluous unreacted monomer content which ultimately affects glistening property of the lens and amount of undesired leachable (extractable) impurities.
WO 1999/007756 discloses high refractive index copolymer compositions suitable for use in ophthalmic lenses, such as foldable intraocular lenses, consisting of conventional aromatic monomer and diacrylate oligomers such as epoxy acrylate, acrylated acrylics. WO 1999/007756 is silent with respect to several factors such as tackiness (stickiness, adhesiveness) of the resulting lenses resulting from monomers having a low Tg, internal reflection resulting from monomers having a high RI, and manufacturing process related internal stresses which results in non-linear heterogeneous mechanical/optical behavior of lenses.
U.S. Pat. No. 7,585,900 discloses soft, high refractive index, acrylic materials (polyethyl/methacrylate, PEA/PEMA) useful as intraocular lens materials, containing an aryl acrylic hydrophobic monomer as the single principal device-forming monomer and a tack-reducing macromer additive (diacrylated polydimethyl siloxane, PDMS). However, PDMS requires custom complex syntheses leading to higher production costs.
U.S. Pat. No. 5,331,073 discloses high refractive index polymeric compositions and foldable intraocular lenses made from such compositions. However, these acrylic-based polymeric compositions include fluorine-containing monomers to rectify tackiness, which are costly and present some biocompatibility issues.
U.S. Pat. No. 5,674,960 discloses PEA/PEMA-based high refractive index polymeric compositions, however, these compositions result in devices that suffer from internal reflection and persistent vacuoles in the ophthalmic implants made therefrom.
EP 1030194 discloses polymeric compositions for soft, transparent and flexible intraocular lens, based on combinations of aryl acrylate and hydrophilic monomer, wherein the content of the hydroxyalkyl acrylate monomer is at least 50%, rendering it too hydrophilic for compatible contact or implantable lenses.
U.S. Pat. No. 6,653,422 discloses soft, high refractive index, polymeric compositions for soft intraocular lenses, having an elongation of at least 150%, constituting of aromatic monomers such as 4-phenyl butyl acrylate, 3-benzyloxypropyl methacrylate in addition to PEA/PEMA.
U.S. Pat. No. 5,693,095 discloses polymeric compositions for foldable ophthalmic lenses, comprising hydrophilic and hydrophobic aromatic acrylic component.
U.S. Patent Application Publication No. 2008139769 discloses (meth)acrylate copolymer compositions for soft intraocular lenses, obtained by copolymerization of a monomer mixture containing aromatic acrylic hydrophilic components along with hydrophobic components.
WO 2004/029675 teaches the formation of intraocular lenses through a process of pre-gel formation and in fused silica mold and a process of casting and extraction.
U.S. Pat. No. 7,304,117 teaches diphenyl azo-based reactive yellow dyes and a process for preparing polymers using the same in the manufacturing of ophthalmic devices, such as intraocular lenses, having blue light absorption properties. Said polymers are capable of blocking blue light from reaching the retina of an eye implanted with the ophthalmic device, and thereby preventing potential damage to the retina.
U.S. Pat. No. 5,433,746 discloses polymer composition constituting aromatic monomers like PEA/PEMA and the likes.
Implantable ophthalmic devices must overcome such issues as cytotoxicity and biocompatibility, which may arise from leachable (extractible) contaminants, hence all ophthalmic devices should be free from leachable contaminants. To reduce these preexisting impurities, extraction steps are typically carried out. WO 2004/029675, U.S. Patent Application Publication Nos. 2005258096, 2004031275and 2003116873 disclose such extraction methods; however, such batch extraction methods suffer from various process complexities and solvent issue.
U.S. Pat. No. 5,603,774 teaches reduction of the tackiness associated with certain such soft acrylic polymers useful for foldable intraocular lenses (IOLs), by plasma treatment of the polymer surface.
Additional background art includes U.S. Pat. Nos. 7,585,900, 5,693,095, 5,290,892, 5,403,901, 5,433,746, 5,674,960, 5,716,403, 5,861,031, 4,304,895 and 4,528,311, U.S. Patent Application Publication Nos. 2003130460, 2009132039, 2008269884, 2003130460, 2008139769, 2008021129, 2001014824, 2003116873 and 2005258096, WO 2001/018079, WO 2006/210438, WO 2006/187042, WO 1999/07756, WO 2009/137525, WO 2009/120511, WO 20008/011566, WO 2008/011564, WO 2001/018079, WO 2001/018078, WO 1999/007756, WO 2004/11764, WO 2004/029675,WO 2004/031275, WO 2009/104516, WO 2006/095750, WO 2009/025399, JP 2003119226, KR 20090047478, EP 1857477, CN101137684.
Light and oxygen induce degradation reactions in polymer-based devices that may not only modify them visually but also exert a detrimental influence on numerous mechanical, physical and optical properties. Such adverse effects can be minimized by use of light stabilizers which are chemical compounds able to interface with the physical and chemical process of light induced degradation.
Radiation reaching the surface of the earth is composed of direct sunlight and scattered light, and the ultraviolet (UV) part of the radiation spectrum is the part that is considered responsible for polymer degradation. The Environmental Protection Agency (EPA or USEPA) designates sub-ranges of ultraviolet light as UVA (315-400 nm), UVB (280-315 nm) and UVC (10-280 nm). UVC and partly UVB rays are absorbed in the oxygen and ozone containing layer located in stratosphere, therefore only part of UVB and UVA radiation reaches the surface of the earth, and constitutes the main factor in aging for polymer-based systems. However, thinning of ozone layer is shifting UV spectral composition towards shorter wavelengths. It is accepted that UV radiation in the range of 280-380 nm, which corresponds to 420-320 kJ, is responsible for polymer degradation. This energy is sufficient to break C—C, C—H, C—O, C—Cl, C—N covalent bonds, hence signifies the need of using light stabilizers in ophthalmic devices which are exposed to direct or indirect sun-light.
UV light is also damaging to living cells, and among these, cell that enable vision. Visible violet light contributes only 5% to scotopic vision (the monochromatic vision of the eye in dim light) but it is responsible for up to 14% UV blue phototoxicity (a phenomenon known in live-cell, where illuminating a fluorescent molecule or a fluorophore, causes the selective death of the cells that express this fluorophore). Ultraviolet radiation may also contribute to the development of ocular disorders such as cataract, ocular cancers, photokeratitis, macular degeneration and corneal degenerative changes (e.g. pterygium, droplet climatic keratopathy, pinguecula), retinitis pigmentosa, night blindness, cystoid macular oedema, solar retinopathy (damage to the eye's retina, particularly the macula, from prolonged exposure to solar radiation), ocular melanomas and like damages.
Photokeratitis (also known as welder's flash or arc eye) is an inflammation of the cornea caused by a brief exposure to UV radiation. Like sunburn, it may be painful and may create symptoms including red eyes, a foreign body sensation or gritty feeling in the eyes, extreme sensitivity to light and excessive tearing. Scientific studies and research growing out of the U.S. space program have shown that exposure to small amounts of UV radiation over a period of many years may increase the chance of developing a cataract, and may cause damage to the retina, the nerve-rich lining of the eye that is used for seeing. Retina damage is usually not reversible, and cumulative damage of repeated exposure may contribute to chronic eye disease, as well as increase the risk of developing skin cancer around the eyelids. Long-term exposure to UV light is also a risk factor in the development of pterygium (a growth that invades the corner of the eyes) and pinguecula (a yellowish, slightly raised lesion that forms on the surface tissue of the white part of the eye).
Ultraviolet light (higher energy with respect to visible light) can be damaging to the light receptor cells. With a few exceptions (e.g., snakes, placental mammals), most organisms avoid these effects by having absorbent oil droplets around their cone cells. The alternative, developed by organisms that had lost these oil droplets in the course of evolution, is to make the lens impervious to UV light, precluding the possibility of UV light being detected, as it does not reach the retina. In the human and other animal eye, UV light is absorbed by molecules known as chromophores, which are present in the eye cells and tissues. Chromophores absorb light energy from the various wavelengths at different rates; a pattern known as absorption spectrum. Furthermore, natural chromophores found in the eye block UV light by fluorescence.
Transparent polymer-based ophthalmic devices are most sensitive to UV light, including visible violet light (400-440 nm). Most of the ophthalmic device research and manufacturing companies incorporate synthetic UV-blockers/absorbers (also referred to herein as light stabilizing additives or light stabilizers) in their ophthalmic devices. The primary function of light stabilizers is to protect the substance from the long-term degradation effects from light, most frequently ultraviolet light. Different UV stabilizers are utilized depending upon the substrate, intended functional life, and sensitivity to UV degradation. UV stabilizers, such as hydroxyphenyl-benzotriazole, hydroxyphenyl-triazine and benzophenone-based light stabilizers, act by absorbing the UV radiation and preventing the formation of, or scavenging, free radicals. Depending upon substitution, the UV absorption spectrum is changed to match the application, while their concentrations typically range from 0.05% to 5% by weight of the polymer.
Unlike naturally occurring chromophores, synthetic dyes used as UV-blockers for incorporation in transparent polymer-based ophthalmic devices typically do not show any kind of fluorescence, hence are less effective in blocking UV radiation than naturally occurring UV-blockers. Furthermore, synthesis of organic UV-blockers/absorbers intended for incorporation into transparent polymer-based ophthalmic devices involves complex, multi-step and costly manufacturing process, which limits the choice of the polymer to great extent. In addition to their production limits, synthetic light stabilizing additives may lack biocompatibility to some extent, and as such may cause the development of hypersensitivity of the epithelium cell layers after prolonged contact therewith, and may cause impairment of scotopic vision.
Moreover, in the case of implantable ophthalmic devices, the thickness of a typical device is required to be kept at a minimum for the sake of smaller incisions. In addition, the concentration of any potentially harmful UV-blockers must be kept at the lowest. Thus, since there is a direct link between the UV-blocking effect and the amount of UV-blocker in the path of the light, UV-blockers are required to have a large cross-section for interaction with the incoming UV radiation. UV-blockers with a relatively low cross-section are less suitable for use in transparent polymer-based ophthalmic devices since they require a long light-path and/or a high concentration in the transparent polymer-based ophthalmic device in order to block UV effectively.
U.S. Pat. Nos. 5,234,990 and 5,578,676 teach compositions for forming anti-reflective layers for DUV microlithographic processes, which include polysulfone and polyurea polymers that possess inherent light absorbing properties at deep ultraviolet wavelengths. These compositions are applied to a substrate to form an anti-reflective coating, and thereafter a photoresist material that is compatible with the anti-reflective coating is applied. These polymers are said to include an additive such as 4,4,-bis(N,N-dimethylamino)benzophenone, 7-diethylamino-4-methylcoumarian, curcumin, 3-aminopropyltriethoxysilane or (3-glycidoxypropyl)trimethoxysilane. These polymers are also said to be opaque, hence are not suitable for use in ophthalmic devices.
U.S. Pat. No. 7,304,117 teaches novel azo-based reactive yellow dyes and a process for manufacturing polymers, using the same in the manufacturing of ophthalmic devices, such as intraocular lenses, having blue light absorption properties. Said polymers are capable of blocking blue light from reaching the retina of an eye implanted with the ophthalmic device, and thereby preventing potential damage to the retina.
U.S. Patent Application Publication No. 20070204412 teaches transparent silicone polymers and elastomers colored by curcumin and/or a derivative therefore.